Cancer treatments have achieved an innovative level of progress in recent years and, especially, an improvement in the success rate of primary carcinoma removal by surgery or radiotherapy has significantly contributed to the progress in cancer treatments. Nonetheless, there are not but a few cases of death by relapse due to metastases of cancers in spite of complete removal of primary carcinomas. A limitation is therefore imposed on the complete prevention of advances of cancers by surgery or radiotherapy.
There is accordingly a growing recognition that the prevention of metastasis of a cancer is an important theme to be achieved for the treatment of the cancer, and clinical tests of cancerous metastasis inhibitors are now under way in the United States, Great Britain, etc.
As a mechanism of hematogenous metastasis of a cancer, the metastasis is assumed to take place through a process which comprises (1) growth of carcinoma cells in a primary carcinoma lesion, (2) development of blood vessels, (3) infiltration of developed blood vessels by malignant carcinoma cells, followed by their penetration into the blood vessels, (4) circulation through the body, (5) arrival at and bonding to a target site, (6) infiltration to the outside of the blood vessels, (7) growth in a target organ, and (8) formation of a metastasized lesion.
As a cancerous metastasis inhibitor, it is generally desirable not only to prevent metastasis of carcinoma cells beforehand but also to prevent proliferation and metastasis of a small metastasized lesion already formed. Those currently available as chemotherapeutic agents for cancers (antitumor agents) on the market are used as drugs effective for the phase (1) in that they exhibit direct growth inhibition and cytocidal activity against carcinoma cells while bringing about size reductions of tumors. They are however not satisfactory drugs as cancerous metastasis inhibitors in that they cause various side effects led by myelotoxicity and exhibit substantially no activity against the other metastasis phases.
Accordingly, drugs of such a new type as having less side effects and permitting long-term administration in view of the process of metastasis are highly valued as cancerous metastasis inhibitors. Clinically, there is also a demand for such drugs.
The blood vessel development phase (2) has therefore been attracting interests as an important target phase for the inhibition of metastasis in recent years in that, except for the growth of a cancer, it takes place only in special cases such as wound healing, resulting in active developments of angiogenesis-inhibiting drugs as metastasis inhibitors.
Various factors are considered to take part in angiogenesis. Platelet-derived endothelial cell growth factor (PD-ECGF) [Nature, 338, 557-562 (1989)], one of such factors, has been reported to be genetically identical human thymidine phosphorylase in recent years [Nature, 356, 668 (1992)]. Thymidine phosphorylase is an enzyme essential for the metabolism of thymidine, and its development in various tissues (livers, lungs, small intestines, large intestines, placentas, etc.) of human and diverse animals has been confirmed. It has also been reported that in a malignant tumor, its development is promoted in the tumored part compared with its adjacent normal tissue [Biochimica et Biophysica Acta, 1034, 107-113 (1992)] and that this thymidine phosphorylase is also developed very often in clinical samples of human tumors and its development is in a positive correlation with the number of blood vessels in a tumor [Cancer Letters, 95, 57-62 (1995)]. As is appreciated from the foregoing, thymidine phosphorylase/PD-ECGF is considered to have close connection with angiogenesis associated with the growth of a tumor. For the induction of angiogenesis by thymidine phosphorylase, its enzymatic activity has been proven to be indispensable, thereby indicating the possibility of suppression of angiogenesis by inhibiting the enzymatic activity [Cancer Research, 55, 1687-1690 (1995)]. Reported as thymidine phosphorylase inhibitors to date include 6-amino-5-bromo-uracil and 6-aminothimine [Biochemical Pharmacology, 29, 1059 (1980)], 6-amino-5-chlorouracil and 3-cyano-2,6-dihydroxypyridine [JP Kokai 63-250324], and acyclothymidine [J P Kokai 5-213761]. Their inhibitory effects are however not sufficient, and it is the current circumstances that no metastasis inhibitor has been found yet for the suppression of angiogenesis induced by thymidine phosphorylase.
Accordingly, an object of the present invention is to provide a cancerous metastasis inhibitor having excellent inhibitory activity against thymidine phosphorylase.